Angiogenesis is the formation of new blood vessels out of pre-existing capillaries and is a sequence of events that is of key importance in many physiologic and pathologic processes. Normal tissue growth, such as in embryonic development, wound healing, and the menstrual cycle, is characterized by dependence on new vessel formation for the supply of oxygen and nutrients as well as removal of waste products. A large number of different and unrelated diseases are also associated with formation of new vasculature. Among certain pathologies are conditions in which angiogenesis is low, and should be enhanced to improve disease conditions. Pathologies which involve inadequate blood vessel formation include peripheral and coronary ischemia and infarction, chronic wound healing failure, and ulcer's. More frequently, however, excessive angiogenesis is an important characteristic of various pathologies including pathologies characterized or associated with an abnormal or uncontrolled proliferation of cells. Pathologies which involve excessive angiogenesis include, for example, cancer (both solid and hematologic tumors), cardiovascular diseases (such as atherosclerosis and restenosis), chronic inflammation (rheumatoid arthritis, Crohn's disease), diabetes (diabetic retinopathy), psoriasis, endometriosis, neovascular glaucoma and adiposity. See Griffioen & Molema, Angiogenesis: Potentials for Pharmacologic Intervention in the Treatment of Cancer, Cardiovascular Diseases, and Chronic Inflammation, PHARMACOL. REV. 52, 237-268 (2000).
Generally speaking, the angiogenic process entails the proliferation and migration of a normally quiescent endothelium, the controlled proteolysis of the pericellular matrix, and the synthesis of new extracellular matrix components by developing capillaries. The establishment of new intra- and intercellular contacts and the morphological differentiation of endothelial cells to capillary-like tubular networks provide support for their subsequent maturation, branching, remodeling and selective regression to form a highly organized, functional microvascular network. The autocrine, paracrine and amphicrine interactions of the vascular endothelium with its surrounding stromal components, as well as with the pro-angiogenic and angiostatic cytokines and growth factors orchestrating physiologic angiogenesis, are normally tightly regulated both spatially and temporally. See Gasparini, The Rationale and Future Potential of Angiogenesis Inhibitors in Neoplasia, DRUGS, 58(1):17-38 (1999)
The best known anti-angiogenic agents targeting endothelial cell proliferation are Vascular Endothelial Growth Factor (“VEGF”) inhibitors. VEGF, a potent angiogenic growth factor, is over expressed in most human solid tumors and in the retina associated eye disorders. The VEGF receptors are mainly enriched in endothelial cells transducing VEGF signaling in many pathological angiogenesis conditions. Growth-stimulated endothelial cells are also sensitive to tyrosine kinase inhibitors targeting VEGF receptors, such as the recent FDA approved anti-cancer drugs Sunitinib (SU11248) and Srafenib (BAY 43-9006). Anti-VEGF and VEGF receptor agents are able to arrest endothelial cell proliferation and prevent new blood vessel growth. In addition to VEGF, many other growth factors such as fibroblast growth factors (FGFs) and platelet derived growth factors (PDGF) also play important roles in endothelial activation. Recently, resistance to anti-angiogenic agents targeting only VEGF signaling is emerging presumably due to other growth factor mediated alternative signaling pathways.
Angiogenesis is crucial to the growth of neoplastic tissues. For more than 100 years, tumors have been observed to be more vascular than normal tissues. Several experimental studies have suggested that both primary tumor growth and metastasis require neovascularization. In contrast to the well orchestrated process described above for normal tissue growth, the pathologic angiogenesis necessary for active tumor growth is generally sustained and persistent, with the initial acquisition of the angiogenic phenotype being a common mechanism for the development of a variety of solid and hematopoietic tumor types. See Folkman, J., CANCER MEDICINE, 132-152 (5th Ed., B.C. Decker Inc.) (2000). Tumors that are unable to recruit and sustain a vascular network typically remain dormant as asymptomatic lesions in situ. Metastasis is also angiogenesis-dependent—for a tumor cell to metastasize successfully, it generally must gain access to the vasculature in the primary tumor, survive the circulation, arrest in the microvasculature of the target organ, exit from this vasculature, grow in the target organ, and induce angiogenesis at the target site. Thus, angiogenesis appears to be necessary at the beginning as well as the completion of the metastatic cascade.
The criticality of angiogenesis to the growth and metastasis of neoplasms thus provides an optimal potential target for chemotherapeutic efforts. Appropriate anti-angiogenic agents may act directly or indirectly to influence tumor-associated angiogenesis either by delaying its onset (i.e., blocking an “angiogenic switch”) or by blocking the sustained and focal neovascularization that is characteristic of many tumor types. Anti-angiogenesis therapies directed against the tumor-associated endothelium and the multiple molecular and cellular processes and targets implicated in sustained pathologic angiogenesis are being actively evaluated for their safety and efficacy in multiple clinical trials. See Deplanque & Harris, Anti-angiogenic Agents: Clinical Trial Design and Therapies in Development, EUR. J. CANCER, 36: 1713-1724 (2000). However, there has been limited success to date with the discovery and/or identification of safe and/or effective anti-angiogenic agents.